Immunologists have become skilled at enhancing and modifying the immune system to induce an immune response. However, once the immune system has been primed against a specific antigen, it is very difficult to specifically stop that response. In short, we have become very adept at turning the immune system on but are just learning how to turn it off. T cells, especially T helper cells, secrete cytokines which strongly influence the phenotypes and activity of other immune cells. T cell receptors (Tcrs) are responsible for the specificity of T cells and recognize a diverse array of foreign and self antigens. Although dogma states that T cells must recognize peptide antigens bound to MHC, we have shown that Tcrs will also recognize free peptides not bound to MHC. The specific aims of this proposal are to identify Tcr-binding, non-MHC restricted peptides from combinatorial peptide libraries and evaluate the effects they elicit in T cells such as anergy, proliferation or altered cytokine secretion. We hypothesize that T cell function can be controlled to therapeutic advantage with free, Tcr-specific peptides upon binding to T cells. Peptides that mediate these activities could be useful in controlling pathologic T cells in many autoimmune diseases or undesirable cytokine secretion in some infectious diseases. The long-term objectives of this project are to understand how and why the peptides we identify exert biological effects on T cells. We propose to develop panels of peptide ligands that elicit predictable and reproducible effects on T cells with the objective of modulating T cell function. A major strength of this approach is that it is not constrained by MHC binding motifs which means that it is not necessary to first define the specific protein or peptide against which a pathologic T cell is directed.